This IRPG application aims to locate genes with substantial contributions to variation in susceptibility to alcohol dependence and hazardous alcohol consumption. We shall focus initially on genes predicted to influence dependence and consumption through their effects on metabolism and sensitivity to intoxication, using DNA from twins who have a history of alcohol dependence, their co-twins, and control pairs. We shall also test loci in candidate regions identified in COGA and other genome scans. For the past 20 years we have gathered extensive longitudinal data on the drinking habits and problems of 7,000 pairs of Australian adult twins and their relatives. Some 12,000 twins and 3,700 spouses of twins have been assessed using structured diagnostic interviews. For a sub-sample of 3,300 individuals we already have DNA samples and selected genetic marker data, and for another sub-sample of 412 subjects (206 pairs) we have detailed data on alcohol metabolism and reactivity. We shall extend this resource and perform new analyses to elucidate the pathways from genotype, via behavioral and biochemical intervening phenotypes, to alcohol dependence. This application emphasizes fine mapping with closely spaced genetic markers in candidate areas, and location of genes through linkage disequilibrium mapping within families. We shall obtain blood samples from: (a) approximately 1000 AD cases from 910 independent families, and 1000 unrelated controls - for conventional case-control analysis; (b) available parents of AD cases, generating at least 751 trios for transmission disequilibrium testing (TDT); (c) additional informative siblings, generating 73 families of two AD siblings plus both parents (approximately 3800 samples total). Related applications plan a 10cM linkage scan for QTLs using the EDAC sib-pair design (IRPG3, Heath) and larger sibships from the Australian twin cohorts (IRPG2, Todorov) and will provide additional affected siblings for this component. Strengths of this application are: (i) large samples give power to detect small effects; (ii) longitudinal data have already been gathered on multiple aspects of the alcoholic phenotype of the subjects, permitting powerful multivariate linkage and association analyses; (iii) our community based sample gives a population epidemiologic perspective but nevertheless contains substantial numbers of subjects meeting DSM-IV alcohol dependence criteria.